Dataset Information

Nuclear FAM289-Galectin-1 interaction controls FAM289-mediated tumor promotion in malignant glioma.

ABSTRACT: BACKGROUND:FAM92A1-289(abbreviated FAM289) is recognized as one of the newly-discovered putative oncogenes. However, its role and molecular mechanisms in promoting cancer progression has not yet been elucidated. This study was performed to reveal its oncogenic functions and molecular mechanisms in human glioblastoma multiforme (GBM) cell models with knockdown or overexpression of FAM289 in vitro and in vivo. METHODS:To elucidate the molecular mechanisms underlying FAM289-mediated tumor progression, the protein-protein interaction between FAM289 and Galectin-1 was verified by co-immunoprecipitation, followed by an analysis of the expression and activity of Galectin-1-associated signaling molecules. Knockdown and overexpression of FAM289 in glioma cells were applied for investigating the effects of FAM289 on cell growth, migration and invasion. The determination of FAM289 expression was performed in specimens from various stages of human gliomas. RESULTS:FAM289-galectin-1 interaction and concomitant activation of the extracellular signal-regulated kinase (ERK) pathway participated in FAM289-mediated tumor-promoting function. Since the expression of DNA methyl transferase 1 (DNMT1) and DNA methyl transferase 3B (DNMT3B) was regulated by FAM289 in U251 and U87-MG glioma cells, Galectin-1 interaction with FAM289 may promote FAM289 protein into the cell nucleus and activate the ERK pathway, thereby upregulating DNMTs expression. Drug resistance tests indicated that FAM289-mediated TMZ resistance was through stem-like property acquisition by activating the ERK pathway. The correlation between FAM289, Galectin-1 expression and the clinical stage of gliomas was also verified in tissue samples from glioblastoma patients. CONCLUSIONS:Our results suggest that high expression of FAM289 in GBM tissues correlated with poor prognosis. FAM289 contributes to tumor progression in malignant glioma by interacting with Galectin-1 thereby promoting FAM289 protein translocation into the cell nucleus. FAM289 in the nucleus activated the ERK pathway, up regulated DNMTs expression and induced stem-like property gene expression which affects drug resistance of glioma cells to TMZ. This study provided functional evidence for FAM289 to be developed as a therapeutic target for cancer treatment.

SUBMITTER: Guo XR

PROVIDER: S-EPMC6731628 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Nuclear FAM289-Galectin-1 interaction controls FAM289-mediated tumor promotion in malignant glioma.

Guo Xing Rong XR Wu Mu Yu MY Dai Long Jun LJ Huang Yu Y Shan Meng Ye MY Ma Shi Nan SN Wang Jue J Peng Hao H Ding Yan Y Zhang Qiu Fang QF Tang Jun Ming JM Ruan Xu Zhi XZ Li Dong Sheng DS

Journal of experimental & clinical cancer research : CR 20190906 1

<h4>Background</h4>FAM92A1-289(abbreviated FAM289) is recognized as one of the newly-discovered putative oncogenes. However, its role and molecular mechanisms in promoting cancer progression has not yet been elucidated. This study was performed to reveal its oncogenic functions and molecular mechanisms in human glioblastoma multiforme (GBM) cell models with knockdown or overexpression of FAM289 in vitro and in vivo.<h4>Methods</h4>To elucidate the molecular mechanisms underlying FAM289-mediated ...[more]

PMID: 31492191

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Project description:BackgroundHuman mesenchymal stem cell (MSC)-based tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene delivery is regarded as an effective treatment for glioblastoma (GBM). However, adverse-free target site homing of the delivery vehicles to the tumor microsatellite nests is challenging, leading to erroneously sustained released of this suicide protein into the normal brain parenchyma; therefore, limiting off-target cytotoxicity and controlled expression of the suicide inductor is a prerequisite for the safe use of therapeutic stem cells.MethodsUtilizing the intrinsic expression profile of GBM and its elevated expression of TGF-β relative to normal brain tissue, we sought to engineer human adipose-derived MSCs (hAMSC-SBE4-TRAIL) which augment the expression of TRAIL under the trigger of TGF-β signaling. We validated our therapeutic technology in a series of functional in vitro and in vivo assays using primary patient-derived GBM models.ResultsOur current findings show that these biologic delivery vehicles have high tumor tropism efficacy and expression TRAIL gene under the trigger of TGF-β-secreting GBMs, as well as avoid unspecific TRAIL secretion into normal brain tissue. hAMSC-SBE4-TRAIL inhibited the proliferation and induced apoptosis in experimental GBMs both in vitro and in vivo. In addition, our improved platform of engineered MSCs significantly decreased the tumor volume and prolonged survival time in a murine model of GBM.ConclusionsOur results on the controlled release of suicide inductor TRAIL by exploiting an endogenous tumor signaling pathway demonstrate a significant improvement for the clinical utility of stem cell-mediated gene delivery to treat brain cancers. Harvesting immune-compatible MSCs from patients' fat by minimally invasive procedures further highlights the clinical potential of this approach in the vision of applicability in a personalized manner. The hAMSC-SBE4-TRAIL exhibit great curative efficacy and are a promising cell-based treatment option for GBM to be validated in clinical exploration.

Project description:Conventional therapies for malignant gliomas (MGs) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by non-specific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in MGs and other neoplasms. This mutation encodes a constitutively active tyrosine kinase that enhances tumorgenicity and migration and confers radiation and chemotherapeutic resistance. This in-frame deletion mutation splits a codon resulting in the creation of a novel glycine at the fusion junction between normally distant parts of the molecule and producing a sequence re-arrangement which creates a tumor-specific epitope for cellular or humoral immunotherapy in patients with MGs. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction is an efficacious immunotherapy in syngeneic murine models, but patients with MGs have a profound immunosuppression that may inhibit the ability of antigen presenting cells (APCs), even those generated ex vivo, to induce EGFRvIII-specific immune responses. In this report, we summarize our results in humans targeting this mutation in two consecutive and one multi-institutional Phase II immunotherapy trials. These trials demonstrated that vaccines targeting EGFRvIII are capable of inducing potent T- and B-cell immunity in these patients, and lead to an unexpectedly long survival time. Most importantly, vaccines targeting EGFRvIII were universally successful at eliminating tumor cells expressing the targeted antigen without any evidence of symptomatic collateral toxicity. These studies establish the tumor-specific EGFRvIII mutation as a novel target for humoral- and cell-mediated immunotherapy in a variety of cancers. The recurrence of EGFRvIII-negative tumors in our patients, however, highlights the need for targeting a broader repertoire of tumor-specific antigens.

Dataset Information

Nuclear FAM289-Galectin-1 interaction controls FAM289-mediated tumor promotion in malignant glioma.

Publications

Nuclear FAM289-Galectin-1 interaction controls FAM289-mediated tumor promotion in malignant glioma.

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